PROJECT SUMMARY Cardiometabolic diseases (CMDs) disproportionately affect American Indian (AI) populations. Socioeconomic (SE) determinants of health have gained considerable attention as critical risk factors for CMDs, and SE inequity may be a fundamental feature underlying the disparity in CMDs observed in AIs, although this has yet to be investigated. To comprehensively understand the role of the SE environment on CMDs pathogenesis, investigation into the underlying biological mechanisms is needed. Epigenetic mechanisms provide a unique opportunity to identify plausible mechanisms of this relationship, given they facilitate gene-environment interactions. The proposed project will combine multi-level socioecological information with epigenomic and inflammatory proteomic data to understand the complex relationship between the SE environment and endogenous responses that may underlie CMDs and CMD-associated risk phenotypes. This project will leverage rich data collected from the largest longitudinal, prospective cohort of AIs in the U.S., the Strong Heart Family Study (SHFS), an extension of the original Strong Heart Study, which includes AI communities across Arizona, Oklahoma, and North/South Dakota. During the K99 phase, we will build upon the rich data collected in the SHFS by creating personal, neighborhood and cumulative measures of SE adversity from participants in the SHFS cohort at SHFS baseline (Visit 4; 2001-2003) and follow-up (Visit 5; 2005-2009); and we will investigate SE determinants of cardiometabolic health (Aim 1). In the R00 phase, we will identify biologically relevant DNA methylation alterations and epigenetic aging deviations associated with SE adversity (Aim 2), and we will integrate DNA methylomic and inflammatory proteomic data to identify a biological signature that will better explain SE adversity-induced CMD risk (Exploratory Aim). Dr. Dye will have a dedicated training and career development plan that will supplement the proposed research and build his scientific capacity towards his short- and long-term goals. In addition to didactic training, Dr. Dye will have experiential training and guidance by his mentorship and advisory team of leading experts in fields relevant to this study. Dr. Dye will gain fundamental training in indigenous health disparities research and CMD epidemiology (Dr. Ana Navas-Acien, primary mentor); environmental molecular epidemiology and epigenetics (Dr. Andrea Baccarelli, co-mentor); social epidemiology and determinants of indigenous health disparities (Dr. Mandy Fretts, advisor); and data science approaches to high-dimensional, -omics data (Zhonghua Liu, advisor). This award will prepare Dr. Dye for an independent research career that will bridge epigenetic epidemiology, social epidemiology, and indigenous health sciences for his long-term goals to understand the epigenetic basis of determinants of health in indigenous and under-served communities. This project will be useful for preventative medicine (e.g., policy and interventions) in under-served communities, and identifying biological mechanisms will be invaluable for precision medicine (e.g., therapeutics, diagnostics, prognostics).

PROJECT NARRATIVE American Indians are disproportionately affected by cardiometabolic diseases, and these disparities may be due, in part, to socioeconomic inequities that burden American Indian communities. An understanding of the biological mechanisms that may be involved in the socioeconomic determinants of cardiometabolic health will be instrumental to abrogating cardiometabolic disease disparities in American Indians; thus, this proposal will provide a comprehensive examination of feasible epigenetic mechanisms that may underlie the effects of socioeconomic adversity on cardiometabolic disease risk in American Indians. Findings from this study will improve our understanding into the importance that socioeconomic determinants have on cardiometabolic health in American Indians with relevance to other susceptible populations, and it will provide compelling evidence that will be instrumental towards developing preventative strategies and precision medicine approaches to addressing socioeconomic inequities and cardiometabolic disease disparities.